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PMID: 29290338 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

American journal of human genetics ·Vol. 102 ·No. 1 ·2018-00-04 ·页码 69-87

Koczkowska M, Chen Y, Callens T, Gomes A, Sharp A, Johnson S, Hsiao MC, Chen Z, Balasubramanian M, Barnett CP, Becker TA, Ben-Shachar S, Bertola DR, Blakeley JO, Burkitt-Wright EMM, Callaway A, Crenshaw M, Cunha KS, Cunningham M, D'Agostino MD, Dahan K, De Luca A, Destrée A, Dhamija R, Eoli M, Evans DGR, Galvin-Parton P, George-Abraham JK, Gripp KW, Guevara-Campos J, Hanchard NA, Hernández-Chico C, Immken L, Janssens S, Jones KJ, Keena BA, Kochhar A, Liebelt J, Martir-Negron A, Mahoney MJ, Maystadt I, McDougall C, McEntagart M, Mendelsohn N, Miller DT, Mortier G, Morton J, Pappas J, Plotkin SR, Pond D, Rosenbaum K, Rubin K, Russell L, Rutledge LS, Saletti V, Schonberg R, Schreiber A, Seidel M, Siqveland E, Stockton DW, Trevisson E, Ullrich NJ, Upadhyaya M, van Minkelen R, Verhelst H, Wallace MR, Yap YS, Zackai E, Zonana J, Zurcher V, Claes K, Martin Y, Korf BR, Legius E, Messiaen LM

Abstract

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.

Keywords
CSRD MPNST NF1 codons 844–848 genotype-phenotype correlation missense mutation neurofibromatosis type 1 plexiform neurofibroma spinal NF
MeSH 主题词
Adolescent Amino Acid Sequence Child Codon/genetics Cohort Studies Computer Simulation Demography Female Genetic Association Studies Heterozygote Humans Male Mutation, Missense/genetics Neurofibromatosis 1/genetics Neurofibromin 1/chemistry,genetics Phenotype Young Adult
化学物质
Codon Neurofibromin 1
作者与单位
共 75 位作者,点击展开单位 / ORCID
Koczkowska Magdalena
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Chen Yunjia
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Callens Tom
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Gomes Alicia
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Sharp Angela
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Johnson Sherrell
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Hsiao Meng-Chang
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Chen Zhenbin
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Balasubramanian Meena
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, UK.
Barnett Christopher P
Women's and Children's Hospital/SA Pathology, North Adelaide, SA 5006, Australia.
Becker Troy A
Medical Genetics, John Hopkins All Children's Hospital, St. Petersburg, FL 33701, USA.
Ben-Shachar Shay
The Genetic Institute, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv 6997801, Israel.
Bertola Debora R
Department of Pediatrics, University of São Paulo, São Paulo 05403-000, Brazil.
Blakeley Jaishri O
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Burkitt-Wright Emma M M
Genomic Medicine, Division of Evolution and Genomic Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK.
Callaway Alison
Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK.
Crenshaw Melissa
Medical Genetics, John Hopkins All Children's Hospital, St. Petersburg, FL 33701, USA.
Cunha Karin S
Department of Pathology, School of Medicine, Universidade Federal Fluminense, Niterói 24220-900, Brazil.
Cunningham Mitch
Division of Genetic, Genomic and Metabolic Disorders, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI 48201, USA.
D'Agostino Maria D
Department of Medical Genetics, McGill University Health Centre, Montréal, QC H4A 3J1, Canada.
Dahan Karin
Center for Human Genetics, Institute of Pathology and Genetics (IPG), Gosselies 6041, Belgium.
De Luca Alessandro
Molecular Genetics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy.
Destrée Anne
Center for Human Genetics, Institute of Pathology and Genetics (IPG), Gosselies 6041, Belgium.
Dhamija Radhika
Department of Clinical Genomics and Neurology, Mayo Clinic, Phoenix, AZ 85259, USA.
Eoli Marica
Unit of Molecular Neuro-Oncology, IRCCS Foundation, Carlo Besta Neurological Institute, Milan 20133, Italy.
Evans D Gareth R
Genomic Medicine, Division of Evolution and Genomic Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK.
Galvin-Parton Patricia
Department of Genetics, Stony Brook Children's, Stony Brook, NY 11794, USA.
George-Abraham Jaya K
Dell Children's Medical Center of Central Texas, Austin, TX 78723, USA.
Gripp Karen W
Division of Medical Genetics, Al DuPont Hospital for Children, Wilmington, DE 19803, USA.
Guevara-Campos Jose
Pediatrics Service, Felipe Guevara Rojas Hospital, University of Oriente, El Tigre-Anzoátegui, Venezuela 6034, Spain.
Hanchard Neil A
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Hernández-Chico Concepcion
Department of Genetics, Hospital Universitario Ramón y Cayal, Institute of Health Research (IRYCIS), Madrid 28034, Spain and Center for Biomedical Research-Network of Rare Diseases (CIBERER).
Immken LaDonna
Dell Children's Medical Center of Central Texas, Austin, TX 78723, USA.
Janssens Sandra
Center for Medical Genetics, Ghent University Hospital, Ghent 9000, Belgium.
Jones Kristi J
Department of Clinical Genetics, the Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
Keena Beth A
Division of Human Genetics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Kochhar Aaina
Department of Genetics, Valley Children's Healthcare, Madera, CA 93636, USA.
Liebelt Jan
Women's and Children's Hospital/SA Pathology, North Adelaide, SA 5006, Australia.
Martir-Negron Arelis
Division of Clinical Genetics, Center for Genomic Medicine, Miami Cancer Institute, Miami, FL 33176, USA.
Mahoney Maurice J
Department of Genetics, Yale University, New Haven, CT 06520, USA.
Maystadt Isabelle
Center for Human Genetics, Institute of Pathology and Genetics (IPG), Gosselies 6041, Belgium.
McDougall Carey
Division of Human Genetics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
McEntagart Meriel
St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
Mendelsohn Nancy
Genomics Medicine Program, Children's Hospital Minnesota, Minneapolis, MN 55404, USA.
Miller David T
Multidisciplinary Neurofibromatosis Program, Boston Children's Hospital, Boston, MA 02115, USA.
Mortier Geert
Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium.
Morton Jenny
Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.
Pappas John
Department of Pediatrics, Clinical Genetic Services, NYU School of Medicine, New York, NY 10016, USA.
Plotkin Scott R
Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Pond Dinel
Genomics Medicine Program, Children's Hospital Minnesota, Minneapolis, MN 55404, USA.
Rosenbaum Kenneth
Division of Genetics and Metabolism, Children's National Health System, Washington, DC 20010, USA.
Rubin Karol
University of Minnesota Health, Minneapolis, MN 55404, USA.
Russell Laura
Department of Medical Genetics, McGill University Health Centre, Montréal, QC H4A 3J1, Canada.
Rutledge Lane S
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Saletti Veronica
Developmental Neurology Unit, IRCCS Foundation, Carlo Besta Neurological Institute, Milan 20133, Italy.
Schonberg Rhonda
Division of Genetics and Metabolism, Children's National Health System, Washington, DC 20010, USA.
Schreiber Allison
Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Seidel Meredith
Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Siqveland Elizabeth
Genomics Medicine Program, Children's Hospital Minnesota, Minneapolis, MN 55404, USA.
Stockton David W
Division of Genetic, Genomic and Metabolic Disorders, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI 48201, USA.
Trevisson Eva
Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy and Italy Istituto di Ricerca Pediatria, IRP, Città della Speranza, Padova 35128, Italy.
Ullrich Nicole J
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
Upadhyaya Meena
Division of Cancer and Genetics, Cardiff University, Cardiff CF14 4XN, UK.
van Minkelen Rick
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
Verhelst Helene
Department of Paediatrics, Division of Paediatric Neurology, Ghent University Hospital, Ghent 9000, Belgium.
Wallace Margaret R
Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Yap Yoon-Sim
Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore; Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, SA 5000, Australia.
Zackai Elaine
Division of Human Genetics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Zonana Jonathan
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
Zurcher Vickie
Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Claes Kathleen
Center for Medical Genetics, Ghent University Hospital, Ghent 9000, Belgium.
Martin Yolanda
Department of Genetics, Hospital Universitario Ramón y Cayal, Institute of Health Research (IRYCIS), Madrid 28034, Spain and Center for Biomedical Research-Network of Rare Diseases (CIBERER).
Korf Bruce R
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Legius Eric
Department of Human Genetics, KU Leuven - University of Leuven, Leuven 3000, Belgium.
Messiaen Ludwine M
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: lmessiaen@uabmc.edu.
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
Corresponding email
Published
2018-00-04
电子出版
2017-00-28
页码
69-87
Language
English
Country/Region
United States
NLM ID
0370475
基金资助
NICHD NIH HHS · U54 HD090255 · United States
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